Sepsis ranges from systemic inflammatory response to organ dysfunction to multiple organ failure, and ultimately death. See, e.g., Stone (1994) Science 264: 365-367; Stone (1994) Science 264: 365-367; Karima et al. (1999) Mol. Med. Today 5: 123-132; and Parrillo et al. (1990) Ann Int Med. 113: 227-242). To prevent sepsis, studies have been conducted on compounds including antioxidants, anti-inflammation agents, and inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis. See, e.g., Ortolani et al. (2000) Am J Respir Crit Care Med. 161: 1907-1911; Kox et al. (2000) Intensive Care Med. 26: S124-128; and Boyle et al. (2000) Circ Res 87: E18-24). The results of these studies are not satisfactory (Glauser (2000) Crit Care Med. 28: S4-8).
Some data indicated that large quantities of NO contribute to the pathogenesis of vascular failure in sepsis (Rees (1995) Biochem Soc Trans. 23: 1025-1029). In vivo, large quantities of NO result from: (i) exaggerated synthesis of NO in endothelium after severe attacks such as sepsis, see, e.g., Ochoa et al. (1991) Ann Surg 214: 621-626; Nakatsu & Diamond (1989) Can J Physiol Pharmacol. 67: 251-262; and Guh et al. (1998) Mol. Pharmacol. 53: 467-474; and (ii) up-regulation of the inducible NO synthase (iNOS) as cells respond to bacterial products (e.g., LPS) or inflammatory cytokines (e.g., interleukin-1β and tumor necrosis factor-α), see, e.g., Curran et al. (1989) J Exp Med. 170: 1769-1774; and Nakayama et al. (1992) Am J Respir Cell Mol Biol. 7: 471-476. NO can react with a superoxide to produce peroxynitrite, which accounts for oxidative injury (Szabo (1996) Shock. 6: 79-88). Peroxynitrite has also been reported to be involved in vascular cell apoptosis (Cuzzocrea et al. (1998) Br J Pharmacol. 123: 525-537).
Compounds that inhibit vascular cell apoptosis, and therefore prevent vascular and multiple organ failure, are drug candidates for treating or preventing sepsis or symptoms associated with sepsis.